Morphological analysis at the subcellular level is an essential component of modern cell biology and pathobiology research. Experimental approaches proposed in the projects of the current application include extensive use of microscopic analysis on the morphology of subcellular organelles as well as the use of immuno microscopic analysis at the subcellular level on the pattern and localization of specific mutant proteins and chaperones. We will establish a Morphology Core (Core A) consisting of an electron microscopy (EM) services, as well as a central facility equipped with conventional and confocal microscopes The EM service will be established with Dr. Hans Geuze and Janice Griffith at the University of Utrecht, the Netherlands. Dr. Hans Geuze is an internationally recognized expert in both EM techniques and subcellular morphology. His past collaborations and frequent interactions with the Pis in the current proposal has provided the foundation for efficient operation of the EM service. The conventional and confocal microscopes will be equipped with image analysis systems to facilitate data analysis and publication. The usage of the Morphology Core by various projects will include: 1) immuno localization of protein expression within specific subcellular organelles; 2) immunohistochemical and in situ hybridization analysis of protein/mRNA expression in specific tissues; 3) morphological analysis of subcellular organelles under physiologic and pathologic conditions; and 4) defining protein interactions within intact cells using two-fusion fluorescence resonance energy transfer. The establishment of this core facility will facilitate collaboration among the individual investigators and their projects. By using existing expertise and a centralized facility, this core will also increase the quality and efficiency and decrease the cost of the overall program.